Counter regulatory mechanisms of cardiotonic steroids in cardio-renal syndrome

项目总结 慢性肾脏病(CKD)患者常发展为以舒张期为特征的“尿毒症”心肌病 功能障碍、左心室肥厚和心脏重塑，尽管现代治疗 神经激素阻滞剂。我们已经描述了强心类固醇(CTS)在心脏疾病中的中枢机制作用。 肾损伤后激活促炎和促纤维化通路，加重尿毒症 心肌病。CTS是一类类固醇激素家族，包括蟾酥二烯内酯类化合物，如Marinobufagenin和 端磷脂在CKD等扩容条件下明显升高，并可直接 通过Na+/K+-ATPase结合和信号传递导致炎症和心肌纤维化。 对氧磷酶(PON)是一种水解性乳糖酶，根据其异构体的不同，可在 肝脏和循环与高密度脂蛋白结合或在组织水平的细胞内表达。我们的 初步的实验和临床数据显示，乳糖酶活性降低与 PON与慢性肾脏病心脏疾病严重程度和进展的关系。然而，潜在的心脏保护 机制(S)在很大程度上是未知的。现在，我们第一次发现了新的机械性相互作用 对氧磷酶和内源CTS之间的关系。有趣的是，PON的乳糖酶活性将CTS水解为 它们的开环形式，不像天然的CTS，不能刺激胶原的形成。因此， 这项提案的总体目标是验证PON对心脏保护可以阻止进展心脏的假设 慢性肾脏病的纤维化和舒张期功能障碍，其机制是通过调节发病机制发生的 内源性CTS诱导的信号通路。我们的研究将为无源光网络定义一种新的内源基质，并 首次建立CTS活性在减轻心脏重构中的反向调节机制 在肾功能受损之后。

PROJECT SUMMARY Patients with chronic kidney disease (CKD) often develop a “uremic” cardiomyopathy characterized by diastolic dysfunction, left ventricular hypertrophy, and cardiac remodeling, despite contemporary therapies of neurohormonal blockade. We have described a central mechanistic role of cardiotonic steroids (CTS) in activating pro-inflammatory and pro-fibrotic pathways following renal insult that potentiate this uremic cardiomyopathy. CTS are a family of steroid hormones including bufadienolides such as marinobufagenin and telocinobufagin which are significantly elevated in volume expanded conditions such as CKD and can directly lead to inflammation and cardiac fibrosis upon binding and signaling through the Na+/K+-ATPase. Paraoxonases (PON) are hydrolytic lactonase enzymes that, depending on isoform, are either generated in the liver and circulate bound to high-density lipoprotein or are expressed intracellularly at the tissue level. Our preliminary experimental and clinical data demonstrate an association between diminished lactonase activities of PON and cardiac disease severity and progression in CKD. Yet the underlying cardioprotective mechanism(s) are largely unknown. Now, for the first time, we have identified novel mechanistic interactions between paraoxonases and endogenous CTS. Interestingly, the lactonase activities of PON hydrolyze CTS to their open-ring forms which, unlike native CTS, are incapable of stimulating collagen formation. Hence, the overall goal of this proposal is to test the hypotheses that cardioprotection by PON can deter progressive cardiac fibrosis and diastolic dysfunction in CKD, and that the mechanism occurs via modulation of pathogenetic pathways induced by endogenous CTS. Our studies will define a novel endogenous substrate for PON and establish for the first time a counter-regulatory mechanism of CTS activities in attenuating cardiac remodeling following renal insult.